Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

ABSTRACT

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US03/32222, filed 14 Oct. 2003, which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/419,703, filed 18Oct. 2002.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In type 2 diabetes, or noninsulin dependent diabetesmellitus NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for amelioratingmany symptoms of type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensititization that is observedwith the glitazones. Newer PPAR agonists that are being tested fortreatment of Type II diabetes are agonists of the alpha, gamma or deltasubtype, or a combination of these, and in many cases are chemicallydifferent from the glitazones (i.e., they are not thiazolidinediones).Serious side effects (e.g. liver toxicity) have occurred with some ofthe glitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DP-IV” or“DPP-IV”) enzyme are also under investigation as drugs that may beuseful in the treatment of diabetes, and particularly type 2 diabetes.See for example WO 97/40832, WO 98/19998, U.S. Pat. No. 5,939,560,Bioorg. Med. Chem. Lett., 6: 1163–1166 (1996); and Bioorg. Med. Chem.Lett. 6: 2745–2748 (1996). The usefulness of DP-IV inhibitors in thetreatment of type 2 diabetes is based on the fact that DP-IV in vivoreadily inactivates glucagon like peptide-1 (GLP-1) and gastricinhibitory peptide (GIP). GLP-1 and GIP are incretins and are producedwhen food is consumed. The incretins stimulate production of insulin.Inhibition of DP-IV leads to decreased inactivation of the incretins,and this in turn results in increased effectiveness of the incretins instimulating production of insulin by the pancreas. DP-IV inhibitiontherefore results in an increased level of serum insulin.Advantageously, since the incretins are produced by the body only whenfood is consumed, DP-IV inhibition is not expected to increase the levelof insulin at inappropriate times, such as between meals, which can leadto excessively low blood sugar (hypoglycemia). Inhibition of DP-IV istherefore expected to increase insulin without increasing the risk ofhypoglycemia, which is a dangerous side effect associated with the useof insulin secretagogues.

DP-IV inhibitors also have other therapeutic utilities, as discussedherein. DP-IV inhibitors have not been studied extensively to date,especially for utilities other than diabetes. New compounds are neededso that improved DP-IV inhibitors can be found for the treatment ofdiabetes and potentially other diseases and conditions. The therapeuticpotential of DP-IV inhibitors for the treatment of type 2 diabetes isdiscussed by D. J. Drucker in Exp. Opin. Invest. Drugs, 12: 87–100(2003) and by K. Augustyns, et al., in Exp. Opin. Ther. Patents, 13:499–510 (2003).

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are inhibitors ofthe dipeptidyl peptidase-TV enzyme (“DP-IV inhibitors”) and which areuseful in the treatment or prevention of diseases in which thedipeptidyl peptidase-IV enzyme is involved, such as diabetes andparticularly type 2 diabetes. The invention is also directed topharmaceutical compositions comprising these compounds and the use ofthese compounds and compositions in the prevention or treatment of suchdiseases in which the dipeptidyl peptidase-IV enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to hexahydrodiazepinone compounds usefulas inhibitors of dipeptidyl peptidase-IV. Compounds of the presentinvention are described by structural formula I:

or a pharmaceutically acceptable salt thereof; wherein each n isindependently 0, 1, or 2;

-   Ar is phenyl substituted with one to five R³ substituents;-   R¹ is selected from the group consisting of    -   hydrogen,    -   C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted with        one to five substituents independently selected from halogen,        hydroxy, C₁₋₆ alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and        phenyl-C₁₋₃ alkoxy, wherein alkoxy is unsubstituted or        substituted with one to five halogens,    -   (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted        with one to five substituents independently selected from        halogen, CN, hydroxy, R², OR², NHSO₂R², NR²SO₂R², SO₂R², CO₂H,        and C₁₋₆ alkyloxycarbonyl,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens,    -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted or        substituted with one to three substituents independently        selected from oxo, hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted        or substituted with one to three substituents independently        selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens; and    -   wherein any methylene (CH₂) carbon atom in R¹ is unsubstituted        or substituted with one to two groups independently selected        from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or        substituted with one to five halogens;-   each R³ is independently selected from the group consisting of    -   hydrogen,    -   halogen,    -   cyano,    -   hydroxy,    -   C₁₋₆ alkyl, unsubstituted or substituted with one to five        halogens,    -   C₁₋₆ alkoxy, unsubstituted or substituted with one to five        halogens,    -   carboxy,    -   alkoxycarbonyl,    -   amino,    -   NHR²,    -   NR²R²,    -   NHSO₂R²,    -   NR²SO₂R²,    -   NHCOR²,    -   NR²COR²,    -   NHCO₂R²,    -   NR²CO₂R²,    -   SO₂R²,    -   SO₂NH²,    -   SO₂NBR², and    -   SO₂NR²R²;-   each R² is independently C₁₋₆ alkyl, unsubstituted or substituted    with one to five substituents independently selected from halogen,    CO₂H, and C₁₋₆ alkyloxycarbonyl;-   R⁴ and R⁵ are independently selected from the group consisting of:    -   hydrogen,    -   cyano,    -   carboxy,    -   C₁₋₆ alkyloxycarbonyl,    -   C₁₋₁₀ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, C₁₋₆        alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy,        wherein alkoxy is unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted        with one to five substituents independently selected from        halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens,    -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted or        substituted with one to three substituents independently        selected from oxo, hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted        or substituted with one to three substituents independently        selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens,    -   (CH₂)_(n)CONR⁶R⁷, wherein R⁶ and R⁷ are independently selected        from the group consisting of hydrogen, tetrazolyl, thiazolyl,        (CH₂)_(n)-phenyl, (CH₂)_(n)—C₃₋₆ cycloalkyl, and C₁₋₆ alkyl,        wherein alkyl is unsubstituted or substituted with one to five        halogens and wherein phenyl and cycloalkyl are unsubstituted or        substituted with one to five substituents independently selected        from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein        alkyl and alkoxy are unsubstituted or substituted with one to        five halogens;        -   or wherein R⁶ and R⁷ together with the nitrogen atom to            which they are attached form a heterocyclic ring selected            from azetidine, pyrrolidine, piperidine, piperazine, and            morpholine; and wherein said heterocyclic ring is            unsubstituted or substituted with one to five substituents            independently selected from halogen, hydroxy, C₁₋₆ alkyl,            and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted            or substituted with one to five halogens; and wherein any            methylene (CH₂) carbon atom in R⁴ or R⁵ is unsubstituted or            substituted with one to two groups independently selected            from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or            substituted with one to five halogens; and-   R⁸ and R⁹ are each independently hydrogen or C₁₋₆ alkyl.

In one embodiment of the compounds of the present invention, the carbonatom marked with an * has the R configuration as depicted in formula Ia

wherein Ar, R¹, R⁴, R⁵, R⁸, and R⁹ are as defined herein.

In a second embodiment of the compounds of the present invention, R³ isselected from the group consisting of

-   -   hydrogen,    -   halogen,    -   cyano,    -   hydroxy,    -   C₁₋₆ alkyl, unsubstituted or substituted with one to five        halogens, and    -   C₁₋₆ alkoxy, unsubstituted or substituted with one to five        halogens.        In a class of this embodiment, R³ is selected from the group        consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl,        and methyl. In a subclass of this class, R³ is selected from the        group consisting of hydrogen, fluoro, and chloro.

In a third embodiment of the compounds of the present invention, R¹ isselected from the group consisting of:

-   -   hydrogen,    -   C₁₋₆ alkyl, wherein alkyl is unsubstituted or substituted with        one to five substituents independently selected from halogen,        hydroxy, C₁₋₆ alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and        phenyl-C₁₋₃ alkoxy, wherein alkoxy is unsubstituted or        substituted with one to five halogens,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted        or substituted with one to three substituents independently        selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens; and    -   wherein any methylene (CH₂) carbon atom in R¹ is unsubstituted        or substituted with one to two groups independently selected        from halogen, hydroxy, and C₁₋₄ alkyl unsubstituted or        substituted with one to five halogens.

In a class of this embodiment of the compounds of the present invention,R¹ is selected from the group consisting of

-   -   hydrogen,    -   C₁₋₄ alkyl,    -   2,2,2-trifluoroethyl,    -   methoxycarbonylmethyl,    -   carboxymethyl,    -   hydroxyethyl,    -   benzyloxymethyl,    -   benzyloxyethyl, and    -   cyclopropyl.

In a subclass of this class, R¹ is selected from the group consisting ofhydrogen, methyl, tert-butyl, and cyclopropyl.

In a fourth embodiment of the compounds of the present invention, R⁴ andR⁵ are independently selected from the group consisting of:

-   -   hydrogen,    -   C₁₋₁₀ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, C₁₋₆        alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy,        wherein alkoxy is unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted        with one to five substituents independently selected from        halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens,    -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted or        substituted with one to three substituents independently        selected from oxo, hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted        or substituted with one to three substituents independently        selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens,    -   wherein any methylene (CH₂) carbon atom in R⁴ or R⁵ is        unsubstituted or substituted with one to two groups        independently selected from halogen, hydroxy, and C₁₋₄ alkyl        unsubstituted or substituted with one to five halogens.

In a class of this embodiment of the compounds of the present invention,it R⁴ and R⁵ are independently selected from the group consisting of:

-   -   hydrogen,    -   C₁₋₆ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, C₁₋₆        alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy,        wherein alkoxy is unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted        with one to five substituents independently selected from        halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted        or substituted with one to three substituents independently        selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five halogens, and    -   wherein any methylene (CH₂) carbon atom in R⁴ or R⁵ is        unsubstituted or substituted with one to two groups        independently selected from halogen, hydroxy, and C₁₋₄ alkyl        unsubstituted or substituted with one to five halogens.

In a subclass of this class, R⁴ and R⁵ are independently selected fromthe group consisting of:

-   -   hydrogen,    -   CH₃,    -   CH₂CH₃,    -   CH₂CH(CH₃)₂,    -   CH₂-cyclopropyl,    -   CH₂-cyclohexyl,    -   CH₂OCH₂Ph,    -   CH₂OH    -   CH₂Ph,    -   CH₂(3-OCF₃-Ph),    -   CH₂(4-OCF₃-Ph),    -   CH₂(3-CF₃,5-CF₃-Ph),    -   CH₂(2-CF₃-Ph),    -   CH₂(2-Cl-Ph),    -   CH₂(2-Me-Ph),    -   CH₂(2-Me,5-Me-Ph),    -   CH₂(2-Ph-Ph),    -   CH₂(2-F,5-F-Ph),    -   CH₂(2-F-Ph),    -   CH₂(2-F,3-F-Ph),    -   CH₂(2-pyridinyl),    -   CH₂(3-pyridinyl),    -   CH₂(4-pyridinyl),    -   CH₂(1-oxidopyridin-2-yl),    -   CH₂(1-oxidopyridin-3-yl),    -   CH₂(1H-pyrazol-1-yl),    -   CH₂(2-F,6-F-Ph), and    -   CH₂CF₃.

In a further subclass of this class, R⁵ is hydrogen.

In a fifth embodiment of the compounds of the present invention, R⁸ andR⁹ are independently selected from hydrogen and methyl.

In a class of this embodiment, RS and R⁹ are hydrogen.

In a sixth embodiment of the present invention are compounds of formulaIa

-   wherein R¹ is selected from the group consisting of    -   hydrogen,    -   C₁₋₄ alkyl,    -   2,2,2-trifluoroethyl,    -   methoxycarbonylmethyl,    -   carboxymethyl,    -   hydroxyethyl,    -   benzyloxymethyl,    -   benzyloxyethyl, and    -   cyclopropyl;-   R³ is hydrogen, chloro, or fluoro;-   R⁴ is selected from the group consisting of:    -   hydrogen,    -   CH₃,    -   CH₂CH₃,    -   CH₂CH(CH₃)₂,    -   CH₂-cyclopropyl,    -   CH₂-cyclohexyl,    -   CH₂OCH₂Ph,    -   CH₂OH    -   CH₂Ph,    -   CH₂(3-OCF₃-Ph),    -   CH₂(4-OCF₃-Ph), and    -   CH₂(3-CF₃,5-CF₃-Ph)    -   CH₂(2-CF₃-Ph),    -   CH₂(2-Cl-Ph),    -   CH₂(2-Me-Ph),    -   CH₂(2-Me,5-Me-Ph),    -   CH₂(2-Ph-Ph),    -   CH₂(2-F,5-F-Ph),    -   CH₂(2-F-Ph),    -   CH₂(2-F,3-F-Ph),    -   CH₂(2-pyridinyl),    -   CH₂(3-pyridinyl),    -   CH₂(4-pyridinyl),    -   CH₂(1-oxidopyridin-2-yl),    -   CH₂(1-oxidopyridin-3-yl),    -   CH₂(1H-pyrazol-1-yl),    -   CH₂(2-F,6-F-Ph), and    -   CH₂CF₃; and-   R⁸ and R⁹ are hydrogen.

In a class of this embodiment, R⁵ is hydrogen.

Illustrative, but nonlimiting examples, of compounds of the presentinvention that are useful as inhibitors of dipeptidyl peptidase-IV arethe following:

or a pharmaceutically acceptable salt thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC₃₋₁₀, the term alkyl also includes cycloalkyl groups, and combinationsof linear or branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C₁₋₆ is intended.

“Cycloalkyl” is a subset of alkyl and means a saturated carbocyclic ringhaving a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. A cycloalkyl group generally is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₆ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₆ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6–10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

“Heterocycle” and “heterocyclyl” refer to saturated or unsaturatednon-aromatic rings or ring systems containing at least one heteroatomselected from O, S and N, further including the oxidized forms ofsulfur, namely SO and SO₂. Examples of heterocycles includetetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls thus includes heteroaryls fused to other kinds of rings,such as aryls, cycloalkyls and heterocycles that are not aromatic.Examples of heteroaryl groups include: pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups,rings and ring systems containing from 3–15 atoms are included, forming1–3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. The compounds of the present invention have oneasymmetric center at the carbon atom marked with an * in formula Ia.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthis invention. The present invention is meant to comprehend all suchisomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formula Ia shows the preferred sterochemistryat the carbon atom to which is attached the amino group of the betaamino acid from which these compounds are prepared.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediaamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetateor maleate, can be employed. Included are those esters and acyl groupsknown in the art for modifying the solubility or hydrolysischaracteristics for use as sustained-release or prodrug formulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-IV enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-IVenzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-IVenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutically acceptable carrier ordiluent.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-IV enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-IV enzyme activity may bedemonstrated by methodology known in the art. Inhibition constants aredetermined as follows. A continuous fluorometric assay is employed withthe substrate Gly-Pro-AMC, which is cleaved by DP-IV to release thefluorescent AMC leaving group. The kinetic parameters that describe thisreaction are as follows: K_(m)=50 μM; k_(cat)=75 s⁻¹;k_(cat)/K_(m)=1.5×10⁶ M⁻¹s⁻¹. A typical reaction contains approximately50 pM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1mg/ml BSA) in a total reaction volume of 100 μl. Liberation of AMC ismonitored continuously in a 96-well plate fluorometer using anexcitation wavelength of 360 nm and an emission wavelength of 460 nm.Under these conditions, approximately 0.8 μM AMC is produced in 30minutes at 25 degrees C. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). Thekinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found tobe in accord with literature values for the native enzyme. To measurethe dissociation constants for compounds, solutions of inhibitor in DMSOwere added to reactions containing enzyme and substrate (final DMSOconcentration is 1%). All experiments were conducted at room temperatureusing the standard reaction conditions described above. To determine thedissociation constants (K_(i)), reaction rates were fit by non-linearregression to the Michaelis-Menton equation for competitive inhibition.The errors in reproducing the dissociation constants are typically lessthan two-fold.

In particular, the compounds of the following examples had activity ininhibiting the dipeptidyl peptidase-IV enzyme in the aforementionedassays, generally with an IC₅₀ of less than about 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors the dipeptidyl peptidase-IV enzyme activity.

Dipeptidyl peptidase-IV enzyme (DP-IV) is a cell surface protein thathas been implicated in a wide range of biological functions. It has abroad tissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DP-IV is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

Accordingly, the subject compounds are useful in a method for theprevention or treatment of the following diseases, disorders andconditions.

Type II Diabetes and Related Disorders: It is well established that theincretins GLP-1 and GEP are rapidly inactivated in vivo by DP-IV.Studies with DP-IV^((−/−))-deficient mice and preliminary clinicaltrials indicate that DP-IV inhibition increases the steady stateconcentrations of GLP-1 and GIP, resulting in improved glucosetolerance. By analogy to GLP-1 and GIP, it is likely that other glucagonfamily peptides involved in glucose regulation are also inactivated byDP-IV (eg. PACAP). Inactivation of these peptides by DP-TV may also playa role in glucose homeostasis. The DP-IV inhibitors of the presentinvention therefore have utility in the treatment of Type II diabetesand in the treatment and prevention of the numerous conditions thatoften accompany Type II diabetes, including Syndrome X (also known asMetabolic Syndrome), reactive hypoglycemia, and diabetic dyslipidemia.Obesity, discussed below, is another condition that is often found withType II diabetes that may respond to treatment with the compounds ofthis invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled or in some casesprevented, by treatment with the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component. In Syndrome X, also known asMetabolic Syndrome, obesity is thought to promote insulin resistance,diabetes, dyslipidermia, hypertension, and increased cardiovascularrisk. Therefore, DP-IV inhibitors may also be useful to treathypertension associated with this condition.

Obesity: DP-IV inhibitors may be useful for the treatment of obesity.This is based on the observed inhibitory effects on food intake andgastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1in humans significantly decreases food intake and slows gastric emptying(Am. J. Physiol., 277: R910–R916 (1999)). ICV administration of GLP-1 inrats and mice also has profound effects on food intake (Nature Medicine,2: 1254–1258 (1996)). This inhibition of feeding is not observed inGLP-1R^((−/−)) mice, indicating that these effects are mediated throughbrain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 isalso regulated by DP-IV. ICV administration of GLP-2 also inhibits foodintake, analogous to the effects observed with GLP-1 (Nature Medicine.6: 802–807 (2000)). In addition, studies with DP-IV deficient micesuggest that these animals are resistant to diet-induced obesity andassociated pathology (e.g. hyperinsulinonemia).Growth Hormone Deficiency: DP-IV inhibition may be useful for thetreatment of growth hormone deficiency, based on the hypothesis thatgrowth-hormone releasing factor (GRF), a peptide that stimulates releaseof growth hormone from the anterior pituitary, is cleaved by the DP-LVenzyme in vivo (WO 00/56297). The following data provide evidence thatGRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitroto generate the inactive product GRF[3-44] (BBA 1122: 147–153 (1992));(2) GRF is rapidly degraded in plasma to GRF[3-44]; this is prevented bythe DP-IV inhibitor diprotin A; and (3) GRF[3-44 ] is found in theplasma of a human GRF transgenic pig (J. Clin. Invest., 83: 1533–1540(1989)). Thus DP-IV inhibitors may be useful for the same spectrum ofindications which have been considered for growth hormone secretagogues.Intestinal Injury: The potential for using DP-IV inhibitors for thetreatment of intestinal injury is suggested by the results of studiesindicating that glucagon-like peptide-2 (GLP-2), a likely endogenoussubstrate for DP-IV, may exhibit trophic effects on the intestinalepithelium (Regulatory Peptides, 90: 27–32 (2000)). Administration ofGLP-2 results in increased small bowel mass in rodents and attenuatesintestinal injury in rodent models of colitis and enteritis.Immunosuppression: DP-IV inhibition may be useful for modulation of theimmune response, based upon studies implicating the DP-IV enzyme in Tcell activation and in chemokine processing, and efficacy of DP-IVinhibitors in in vivo models of disease. DP-IV has been shown to beidentical to CD26, a cell surface marker for activated immune cells. Theexpression of CD26 is regulated by the differentiation and activationstatus of immune cells. It is generally accepted that CD26 functions asa co-stimulatory molecule in in vitro models of T cell activation. Anumber of chemokines contain proline in the penultimate position,presumably to protect them from degradation by non-specificaminopeptidases. Many of these have been shown to be processed in vitroby DP-IV. In several cases (RANTES, LD78-beta, MDC, eotaxin,SDF-1alpha), cleavage results in an altered activity in chemotaxis andsignaling assays. Receptor selectivity also appears to be modified insome cases (RANTES). Multiple N-terminally truncated forms of a numberof chemokines have been identified in in vitro cell culture systems,including the predicted products of DP-IV hydrolysis.

DP-IV inhibitors have been shown to be efficacious immunosuppressants inanimal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DP-IV, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation, 63: 1495–1500 (1997)). DP-IV inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel [Int. J. Immunopharmacology, 19:15–24 (1997) andImmunopharmacology, 40: 21–26 (1998)). DP-IV is upregulated in a numberof autoimmune diseases including rheumatoid arthritis, multiplesclerosis, Graves' disease, and Hashimoto's thyroiditis (ImmunologyToday, 20: 367–375 (1999)).

HIV Infection: DP-IV inhibition may be useful for the treatment orprevention of HIV infection or AIDS because a number of chemokines whichinhibit HIV cell entry are potential substrates for DP-IV (ImmunologyToday 20: 367–375 (1999)). In the case of SDF-1alpha, cleavage decreasesantiviral activity (PNAS, 95: 6331–6 (1998)). Thus, stabilization ofSDF-1alpha through inhibition of DP-IV would be expected to decrease HIVinfectivity.Hematopoiesis: DP-IV inhibition may be useful for the treatment orprevention of hematopoiesis because DP-TV may be involved inhematopoiesis. A DP-IV inhibitor, Val-Boro-Pro, stimulated hematopoiesisin a mouse model of cyclophosphamide-induced neutropenia (WO 99/56753).Neuronal Disorders: DP-IV inhibition may be useful for the treatment orprevention of various neuronal or psychiatric disorders because a numberof peptides implicated in a variety of neuronal processes are cleaved invitro by DP-IV. A DP-IV inhibitor thus may have a therapeutic benefit inthe treatment of neuronal disorders. Endomorphin-2, beta-casomorphin,and substance P have all been shown to be in vitro substrates for DP-IV.In all cases, in vitro cleavage is highly efficient, with k_(cat)/K_(m)about 10⁶ M⁻¹s⁻¹ or greater. In an electric shock jump test model ofanalgesia in rats, a DP-IV inhibitor showed a significant effect thatwas independent of the presence of exogenous endomorphin-2 (BrainResearch, 815: 278–286 (1999)).

Neuroprotective and neuroregenerative effects of DP-IV inhibitors werealso evidenced by the inhibitors' ability to protect motor neurons fromexcitotoxic cell death, to protect striatal innervation of dopaminergicneurons when administered concurrently with MPTP, and to promoterecovery of striatal innervation density when given in a therapeuticmanner following MPTP treatment [see Yong-Q. Wu, et al.,“Neuroprotective Effects of Inhibitors of Dipeptidyl Peptidase-IV InVitro and In Vivo,” Int. Conf. On Dipeptidyl Aminopeptidases: BasicScience and Clinical Applications, Sep. 26–29, 2002 (Berlin, Germany)].

Tumor Invasion and Metastasis: DP-In inhibition may be useful for thetreatment or prevention of tumor invasion and metastasis because anincrease or decrease in expression of several ectopeptidases includingDP-IV has been observed during the transformation of normal cells to amalignant phenotype (J. Exp. Med., 190: 301–305 (1999)). Up- ordown-regulation of these proteins appears to be tissue and cell-typespecific. For example, increased CD26/DP-IV expression has been observedon T cell lymphoma, T cell acute lymphoblastic leukemia, cell-derivedthyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus,DP-IV inhibitors may have utility in the treatment of such carcinomas.Benign Prostatic Haertrophy: DP-IV inhibition may be useful for thetreatment of benign prostatic hypertrophy because increased DP-IVactivity was noted in prostate tissue from patients with BPH (Eur. J.Clin. Chem. Clin. Biochem., 30: 333–338 (1992)).Sperm motility/male contraception: DP-IV inhibition may be useful forthe altering sperm motility and for male contraception because inseminal fluid, prostatosomes, prostate derived organelles important forsperm motility, possess very high levels of DP-IV activity (Eur. J.Clin. Chem. Clin. Biochem., 30: 333–338 (1992)).

Gingivitis: DP-IV inhibition may be useful for the treatment ofgingivitis because DP-IV activity was found in gingival crevicular fluidand in some studies correlated with periodontal disease severity (Arch.Oral Biol. 37: 167–173 (1992)).

Osteoporosis: DP-IV inhibition may be useful for the treatment orprevention of osteoporosis because GIP receptors are present inosteoblasts.

The compounds of the present invention have utility in treating orpreventing one or more of the following conditions or diseases: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type II diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, and otherconditions that may be treated or prevented by inhibition of DP-IV.

The subject compounds are further useful in a method for the preventionor treatment of the aforementioned diseases, disorders and conditions incombination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred.However, the combination therapy may also include therapies in which thecompound of Formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one of more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other dipeptidyl peptidase IV (DP-IV) inhibitors;

(b) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like) and other PPAR ligands, including PPARα/γdual agonists, such as KRP-297, and PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(ii) biguanides such as metformin and phenformin, and (iii) proteintyrosine phosphatase-1B (PTP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide,glyburide, glipizide, glimepiride, and meglitinides, such asrepaglinide;

(e) α-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists such as those disclosed in WO98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as thosedisclosed in WO00/42026 and WO00/59887;

(h) GIP and GIP mimetics such as those disclosed in WO00/58360, and GIPreceptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as KRP-297, (vi) inhibitors ofcholesterol absorption, such as beta-sitosterol and ezetimibe, (vii)acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe, and(viii) anti-oxidants, such as probucol;

(k) PPARδ agonists, such as those disclosed in WO97/28149;

(l) antiobesity compounds such as fenfluramine, dexfenfluramine,phenteimine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists,CB-1 receptor inverse agonists and antagonists, β₃ adrenergic receptoragonists, melanocortin receptor agonists, in particular melanocortin-4receptor agonists, ghrelin antagonists, and melanin-concentratinghormone (MCH) receptor antagonists;

(m) ileal bile acid transporter inhibitors;

(n) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andselective cyclooxygenase-2 inhibitors;

(o) antihypertensive agents such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers(losaitan, candesartan, irbesartan, valsartan, telmisartan, eprosartan),beta blockers and calcium channel blockers; and

(p) glucokinase activators (GKAs).

Dipeptidyl peptidase-IV inhibitors that can be combined with compoundsof structural formula I include those disclosed in WO 03/004498 (16 Jan.2003); WO 03/004496 (16 Jan. 2003); EP 1 258 476 (20 Nov. 2002); WO02/083128 (24 Oct. 2002); WO 02/062764 (15 Aug. 2002); WO 03/000250 (3Jan. 2003); WO 03/002530 (9 Jan. 2003); WO 03/002531 (9 Jan. 2003); WO03/002553 (9 Jan. 2003); WO 03/002593 (9 Jan. 2003); WO 03/000180 (3Jan. 2003); and WO 03/000181 (3 Jan. 2003). Specific DP-IV inhibitorcompounds include isoleucine thiazolidide; NVP-DPP728; P32/98; P93/01;and LAF 237.

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, cannabinoid CB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghreliniantagonists, and melanin-concentrating hormone (MCH) receptorantagonists. For a review of anti-obesity compounds that can be combinedwith compounds of structural formula I, see S. Chaki et al., “Recentadvances in feeding suppressing agents: potential therapeutic strategyfor the treatment of obesity,” Expert Opin. Ther. Patents, 11: 1677–1692(2001) and D. Spanswick and K. Lee, “Emerging antiobesity drugs,” ExpertOpin. Emerging Drugs, 8: 217–237 (2003).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345(1 Jan. 2002) and WO 01/14376 (1 Mar. 2001); and specific compoundsidentified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.

Cannabinoid CB1 receptor antagonists that can be combined with compoundsof formula I include those disclosed in PCT Publication WO 03/007887;U.S. Pat. No. 5,624,941, such as rimonabant; PCT Publication WO02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT Publication WO98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499; U.S.Pat. No. 5,532,237; and U.S. Pat. No. 5,292,736.

Melanocortin receptor agonists that can be combined with compounds ofstructural formula I include those disclosed in WO 03/009847 (6 Feb.2003); WO 02/068388 (6 Sep. 2002); WO 99/64002 (16 Dec. 1999); WO00/74679 (14 Dec. 2000); WO 01/70708 (27 Sep. 2001); and WO 01/70337 (27Sep. 2001) as well as those disclosed in J. D. Speake et al., “Recentadvances in the development of melanocortin-4 receptor agonists,” ExpertOpin. Ther. Patents, 12: 1631–1638 (2002).

The potential utility of safe and effective activators of glucokinase(GKAs) for the treatment of diabetes is discussed in J. Grimsby et al.,“Allosteric Activators of Glucokinase: Potential Role in DiabetesTherapy,” Science, 301: 370–373 (2003).

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds having Formula I with two or more active compounds selectedfrom biguanides, sulfonylureas, MG-CoA reductase inhibitors, PPARagonists, PTP-LB inhibitors, other DP-IV inhibitors, and anti-obesitycompounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the treatment/prevention/suppressionor amelioration of the diseases or conditions for which compounds of thepresent invention are useful. Such other drugs may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion; subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenonirritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouth washes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofdipeptidyl peptidase-IV enzyme activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 mg of the active ingredient, particularly 1.0,5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared from beta aminoacid intermediates such as those of formula II and substitutedhexahydrodiazepinone intermediates such as those of formula III, usingstandard peptide coupling conditions followed by deprotection. Thepreparation of these intermediates is described in the followingSchemes.

where Ar, R¹, R⁴, R⁵, R⁸, and R⁹ are as defined above and P is asuitable nitrogen protecting group such as tert-butoxycarbonyl (BOC),benzyloxycarbonyl (Cbz), or 9-fluorenylmethoxycarbonyl (Fmoc).

Compounds of formula II are commercially available, known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One common route is illustrated inScheme 1. Protected alpha-amino acid 1, which may be commerciallyavailable or readily prepared from the corresponding amino acid byprotection using, for example, di-tert-butyl dicarbonate (for P=BOC),carbobenzyloxy chloride (for P=Cbz), orN-(9-fluorenylmethoxycarbonyloxy)succinimide (for P=Fmoc), is treatedwith isobutyl chloroformate and a base such as triethylamine orN,N-diisopropylethylamine, followed by diazomethane. The resultantdiazoketone is then treated with silver benzoate in a solvent such asmethanol or aqueous dioxane and may be subjected to sonication followingthe procedure of Sewald et al., Synthesis, 837 (1997) in order toprovide the beta amino acid II. As will be understood by those skilledin the art, for the preparation of enantiomerically pure beta aminoacids II, enantiomerically pure alpha amino acids 1 may be used.Alternate routes to the protected beta-amino acid intermediates II canbe found in the following reviews: E. Juaristi, EnantioselectiveSynthesis of β-Amino Acids, Ed., Wiley-VCH, New York: 1997; Juaristi etal., Aldrichimica Acta. 27: 3 (1994); and Cole et al., Tetrahedron. 32:9517 (1994).

Compounds of formula III are commercially available, known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One convenient method wherein R¹is hydrogen is shown in Scheme 2. Amino ester 2, conveniently used asits hydrochloride salt, is condensed with acrylonitrile 3 and the aminogroup of the product formed is protected, for example, as itstert-butoxyl carbonyl (Boc) derivative, to provide 4, which is reducedto the primary amine 5. Cyclization of 5 to N-protectedhexahydrodiazepinone 7 can be conducted by using trimethylaluminum.Alternatively, the amino ester 5 can be hydrolyzed to the acid 6 andcyclized by using amino acid coupling reagents such as EDC to provideintermediate 7. Deprotection, for example, in the case of Boc, bytreatment with acid such as hydrogen chloride in dioxane ortrifluoroacetic acid in dichloromethane, provides Intermediate IIIa.

An alternate method of preparing hexahydrodiazepinone IIIb (wherein R⁵,R⁸, and R⁹ are hydrogen) is shown in Scheme 3. α-Ketoacids 8, such aspyruvic acid, can be 5 condensed with an aminopropionitrile 9 to providethe cyanoethyl oxopropanamides 10, which can be reductively cyclized tohexahydrodiazepinone IIIb with a reducing agent such as platinum oxideand hydrogen.

Hexahydrodiazepinone intermediates III and intermediates for theirsynthesis can be modified in various ways. For example, the amidenitrogen of intermediate 7, prepared as outlined in Scheme 2, can bealkylated by deprotonation with a base such as sodium hydride followedby treatment with an alkyl halide as shown in Scheme 4. Deprotection ofthe resulting intermediate 11 provides intermediate III.

Another such example is illustrated in Scheme 5. Protectedhexahydrodiazepinone 12, which may be prepared as described forIntermediate 11 in Scheme 4 wherein R⁴ and R⁸ are hydrogen, or byprotection of intermediate ma from Scheme 3 wherein R⁵ is hydrogen, canbe alkylated by using bases such as LDA followed by treatment withvarious alkyl halides. The process may be repeated to install a secondalkyl group, R⁸. Deprotection provides Intermediate III.

Intermediates II and III are coupled under standard peptide couplingconditions, for example, using1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole(EDC/HOBT) or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and 1-hydroxy-7-azabenzotriazole (HATU/HOAT) in asolvent such as N,N-dimethylformamide (DMF) or dichloromethane for 3 to48 hours at ambient temperature to provide Intermediate 13 as shown inScheme 6. In some cases, Intermediate Im may be a salt, such as ahydrochloride or trifluoroacetic acid salt, and in these cases it isconvenient to add a base, generally N,N-diisopropylethylamine, to thecoupling reaction. The protecting group is then removed with, forexample, trifluoroacetic acid or methanolic hydrogen chloride in thecase of Boc to give the desired amine I. The product is purified, ifnecessary, by recrystallization, trituration, preparative thin layerchromatography, flash chromatography on silica gel, such as with aBiotage® apparatus, or HPLC. Compounds that are purified by HPLC may beisolated as the corresponding salt. Purification of intermediates isachieved in the same manner.

In some cases the product I or synthetic intermediates illustrated inthe above schemes may be further modified, for example, by manipulationof substituents on Ar, R¹, R⁴, or R⁵. These manipulations may include,but are not limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions that are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid

Step A: (R,S)-N-(tert-Butoxycarbonyl)-2,5-difluorophenylalanine

To a solution of 0.5 g (2.49 mmol) of 2,5-difluoro-DL-phenylalanine in 5mL of tert-butanol were added sequentially 1.5 mL of 2N aqueous sodiumhydroxide solution and 543 mg of di-tert-butyl dicarbonate. The reactionwas stirred at ambient temperature for 16 h and diluted with ethylacetate. The organic phase was washed sequentially with 1N hydrochloricacid and brine, dried over magnesium sulfate and concentrated in vacuo.The crude material was purified by flash chromatography (silica gel,97:2:1 dichloromethane:methanol:acetic acid) to afford the titlecompound.

MS 302 (M+1).

Step B:(R,S)-3-[(tert-Butoxycarbonyl)amino]-1-diazo-4-(2,5-difluoro-phenyl)butan-2-one

To a solution of 2.23 g (7.4 mmol) of(R,S)-N-(tert-butoxycarbonyl)-2,5-difluorophenylalanine in 100 mL ofdiethyl ether at 0° C. were added sequentially 1.37 mL (8.1 mmol) oftriethylamine and 0.931 mL (7.5 mmol) of isobutyl chloroformate and thereaction was stirred at this temperature for 15 min. A cooled etherealsolution of diazomethane was then added until the yellow color persistedand stirring was continued for a further 16 h. The excess diazomethanewas quenched by dropwise addition of acetic acid, and the reaction wasdiluted with ethyl acetate and washed sequentially with 5% hydrochloricacid, saturated aqueous sodium bicarbonate solution and brine, driedover magnesium sulfate and concentrated in vacuo. Purification by flashchromatography (silica gel, 4:1 hexane:ethyl acetate) afforded thediazoketone.

¹H NMR (500 MHz, CDCl₃) δ 7.03–6.95 (m, 1H), 6.95–6.88 (m, 2H), 5.43(bs, 1H), 5.18 (bs 1H), 4.45 (bs, 1H), 3.19–3.12 (m, 1H), 2.97–2.80 (m,1H), 1.38 (s, 9H).

Step C:(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid

To a solution of 2.14 g (6.58 mmol) of(R,S)-3-[(tert-butoxycarbonyl)-amino]-1-diazo-4-(2,5-difluorophenyl)butan-2-onedissolved in 100 mL of methanol at −30° C. were added sequentially 3.3mL (19 mmol) of diisopropylethylamine and 302 mg (1.32 mmol) of silverbenzoate. The reaction was stirred for 90 inin before diluting withethyl acetate and washing sequentially with 2N hydrochloric acid,saturated aqueous sodium bicarbonate, and brine. The organic phase wasdried over magnesium sulfate, concentrated in vacuo and the enantiomerswere separated by preparative chiral HPLC (Chiralpak AD column, 5%ethanol in hexanes) to give 550 mg of the desired (R)-enantiomer, whicheluted first. This material was dissolved in 50 mL of a mixture oftetrahydrofuran:methanol:1N aqueous lithium hydroxide (3:1:1) andstirred at 50° C. for 4 h. The reaction was cooled, acidified with 5%dilute hydrochloric acid and extracted with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate andconcentrated in vacuo to give the title compound as a white foamy solid.

¹ HNMR (500 MHz, CDCl₃) δ 7.21 (m, 1H), 6.98 (m, 2H), 6.10 (bs, 1H),5.05 (m, 1H), 4.21 (m, 1H), 2.98 (m, 2H), 2.60 (m, 2H), 1.38 (s, 9H).

(3R)-3-[(tert-Butoxycarbonyl)amino]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-butanoicacid

Step A:(2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2′-fluoro-4′-(trifluoromethyl)benzyl)-5-isopropylpyrazine

To a solution of 3.32 g (18 mmol) of commercially available(2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL oftetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solutionof butyllithium in hexanes. After stirring at this temperature for 20min, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20mL of tetrahydrofuran was added and stirring was continued for 3 hbefore warming the reaction to ambient temperature. The reaction wasquenched with water, concentrated in vacuo, and extracted with ethylacetate. The combined organic phase was washed with brine, dried, andconcentrated in vacuo. Purification by flash chromatography (silica gel,0–5% ethyl acetate in hexanes) afforded the title compound.

¹H NMR (500 MHz, CDCl₃) δ 7.33–7.25 (m, 3H), 4.35–4.31 (m, 1H), 3.75 (s,3H), 3.65 (s, 3H), 3.60 (t, 1H, J=3.4 Hz), 3.33 (dd, 1H, J=4.6, 13.5Hz), 3.03 (dd, 1H, J=7, 13.5 Hz), 2.25 –2.15 (m, 1H), 1.0 (d, 3H, J=7Hz), 0.66 (d, 3H, J=7 Hz).

Step B:(R)-N-(tert-Butoxycarbonyl)-2-fluoro-4-trifluoromethyl-phenylalaninemethyl ester

To a solution of 5.5 g (15 mmol) of(2R,5S)-2,5-dihydro-3,6-dimethoxy-2-(2′-fluoro-4′-(trifluoromethyl)benzyl)-5-isopropylpyrazinein 50 mL of a mixture of acetonitrile:dichloromethane (10:1) was added80 mL of 1N aqueous trifluoroacetic acid. The reaction was stirred for 6h and the organic solvents were removed in vacuo. Sodium carbonate wasadded until the solution was basic (>pH 8), and then the reaction wasdiluted with 100 mL of tetrahydrofuran and 10 g (46 mmol) ofdi-tert-butyl dicarbonate was added. The resulting slurry was stirredfor 16 h, concentrated in vacuo, and extracted with ethyl acetate. Thecombined organic phase was washed with brine, dried, and concentrated invacuo. Purification by flash chromatography (silica gel, 20% ethylacetate in hexanes) afforded the title compound.

¹H NMR (500 MHz, CDCl₃) δ 7.38–7.28 (m, 3H), 5.10 (bd, 1H), 4.65–3.98(m, 1H) 3.76 (s, 3H), 3.32–3.25 (m, 1H), 3.13–3.05 (m, 1H), 1.40 (s,9H).

Step C:(R)-N-(tert-Butoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenyl-alanine

A solution of 5.1 g (14 mmol) of(R,S)-N-(tert-butoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenylalaninemethyl ester in 350 mL of a mixture of tetrahydrofuran:methanol:1Nlithium hydroxide (3:1:1) was stirred at 50° C. for 4 h. The reactionwas cooled, acidified with 5% hydrochloric acid and extracted with ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate and concentrated in vacuo to give the title compound.

¹H NMR (500 MHz, CD₃OD) δ 7.45–7.38 (m, 3H), 4.44–4.40 (m, 1H),3.38–3.33 (m, 1H), 2.98 (dd, 1H, J=9.6, 13.5 Hz), 1.44 (s, 9H).

Step D:(3R)-3-[(tert-Butoxycarbonyl)amino]-4-[2-fluoro(trifluoromethyl)-phenyl]-butanoicacid

To a solution of 3.4 g (9.7 mmol) of the product from Step C in 60 mL oftetrahydrofuran at 0° C. were added sequentially 2.3 mL (13 mmol) ofdiisopropylethylamine and 1.7 mL (13 mmol) of isobutyl chloroformate andthe reaction was stirred at this temperature for 30 min. A cooledethereal solution of diazomethane was then added until the yellow colorpersisted and stirring was continued for a further 16 h. The excessdiazomethane was quenched by dropwise addition of acetic acid, and thereaction was diluted with ethyl acetate and washed sequentially with 5%hydrochloric acid, saturated aqueous sodium bicarbonate solution andbrine, dried over magnesium sulfate and concentrated in vacuo.Purification by flash chromatography (silica gel, 9:1 hexane:ethylacetate) afforded 0.5 g of diazoketone. To a solution of 0.5 g (1.33mmol) of the diazoketone dissolved in 100 mL of methanol at 0° C. wereadded sequentially 0.7 mL (4 mmol) of diisopropylethylamine and 32 mg(0.13 mmol) of silver benzoate. The reaction was stirred for 2 h beforediluting with ethyl acetate and washing sequentially with 2Nhydrochloric acid, saturated aqueous sodium bicarbonate, and brine. Theorganic phase was dried over magnesium sulfate, concentrated in vacuoand dissolved in 50 mL of a mixture of tetrahydrofuran:methanol:1Naqueous lithium hydroxide (3:1:1) and stirred at 50° C. for 3 h. Thereaction was cooled, acidified with 5% hydrochloric acid and extractedwith ethyl acetate. The combined organic phases were washed with brine,dried over magnesium sulfate and concentrated in vacuo to give the titlecompound as a white foamy solid.

¹H NMR (500 MHz, CD₃OD): δ 7.47–7.33 (m, 3H), 4.88 (bs, 1H), 4.26–3.98(m, 1H), 2.83–2.77 (m, 1H), 2.58–2.50 (m, 2H), 1.29 (s, 9H).

(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid

Step A:(2S,5R)-2,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2′,4′,5′trifluorobenzyl)-pyrazine

The title compound (3.81 g) was prepared from 3.42 g (18.5 mmol) of(2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 5 g (22.3 mmol)of 2,4,5-trifluorobenzyl bromide using the procedure described forIntermediate 2, Step A.

¹H NMR (500 MHz, CDCl₃): δ 7.01 (m, 1H), 6.85 (m, 1H), 4.22 (m, 1H),3.78 (m, 3H), 3.64 (m, 3H), 3.61 (m, 1H), 3.20 (m, 1H), 2.98 (m, 1H),2.20 (m, 1H), 0.99 (d, 3H, J=8 Hz), 0.62 (d, 3H, J=8 Hz).

Step B: (R)-N-(tert-Butoxycarbonyl)-2,4,5-trifluorophenylalanine methylester

To a solution of 3.81 g (11.6 mmol) of (2S,5R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2′,4′,5′trifluorobenzyl)pyrazinein 20 mL of acetonitrile was added 20 mL of 2N hydrochloric acid. Thereaction was stirred for 72 h and concentrated in vacuo. The residue wasdissolved in 30 mL of dichloromethane and 10 mL (72 mmol) oftriethylamine and 9.68 g (44.8 mmol) of di-tert-butyl dicarbonate wereadded. The reaction was stirred for 16 h, diluted with ethyl acetate andwashed sequentially with 1N hydrochloric acid and brine. The organicphase was dried over sodium sulfate, concentrated in vacuo and purifiedby flash chromatography (silica gel, 9:1 hexanes:ethyl acetate) toafford the title compound.

¹H NMR (500 MHz, CDCl₃): δ 6.99 (m, 1H), 6.94 (m, 1H), 5.08 (m, 1H),4.58 (m, 1H), 3.78 (m, 3H), 3.19 (m, 1H), 3.01 (m, 1H), 1.41 (s, 9H).

Step C: (R)-N-(tert-Butoxycarbonyl)-2,4,5-trifluorophenylalanine

The title compound (2.01 g) was prepared from 2.41 g (7.5 mol) of(R)-N-(tert-butoxycarbonyl)-2,4,5-trifluorophenylalanine methyl esterusing the procedure described for Intermediate 2, Step C.

LC-MS 220.9 (M+1-BOC).

Step D:(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)-butanoicacid

To a solution of 0.37 g (1.16 mmol) of(R)-N-(1,1-dimethylethoxy-carbonyl)-2,4,5-trifluorophenylalanine in 10mL of diethyl ether at −20° C. were added sequentially 0.193 mL (1.3mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate,and the reaction was stirred at this temperature for 15 min. A cooledethereal solution of diazomethane was then added until the yellow colorpersisted and stirring was continued for a further 1 h. The excessdiazomethane was quenched by dropwise addition of acetic acid, and thereaction was diluted with ethyl acetate and washed sequentially withsaturated aqueous sodium bicarbonate solution and brine, dried overmagnesium sulfate and concentrated in vacuo. Purification by flashchromatography (silica gel, 3:1 hexane:ethyl acetate) afforded 0.36 g ofdiazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketonedissolved in 12 mL of 1,4-dioxane: water (5:1) was added 26 mg (0.113mmol) of silver benzoate. The resultant solution was sonicated for 2 hbefore diluting with ethyl acetate and washing sequentially with 1Nhydrochloric acid and brine, drying over magnesium sulfate andconcentrating in vacuo. Purification by flash chromatography (silicagel, 97:2:1 dichloromethane:methanol:acetic acid) afforded the titlecompound.

¹H NMR (500 MHz, CDCl₃) δ 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H),4.18 (m, 1H), 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H).

(3R)-4-(2-Bromo-4,5-difluorophenyl)-3-tert-butoxycarbonyl)amino]-butanoicacid

To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid[prepared according to the procedure of Braish et al., Syn. Comm.,3067–3074 (1992)] in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol)of carbonyldiimidazole. The solution was heated under reflux for 3.5 h,cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydridein 15 mL of water was added. The reaction was stirred for 10 min andpartitioned between ethyl acetate and 10% aqueous sodium bicarbonatesolution. The organic layer was washed twice with warm water, brine,dried over magnesium sulfate, and concentrated in vacuo. Purification byflash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethaneat 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10mmol) of triphenylphosphine. The reaction was stirred for 2 h at thistemperature, the solvent was removed in vacuo and the residue stirredwith 100 mL of diethyl ether. The solution was filtered, concentrated invacuo, and purified by flash chromatography (silica gel, 20:1hexane:ethyl acetate) to afford 2.9 g of 2-bromo-4,5-difluorobenzylbromide contaminated with carbon tetrabromide which was used withoutfurther purification. Using the procedures outlined for the preparationof Intermediates 2–4, the benzyl bromide derivative was converted to thetitle compound.

LC-MS 394 and 396 (M+1).

Essentially following the procedures outlined for the preparation ofIntermediates 1–4, the Intermediates in Table 1 were prepared.

TABLE 1

Inter- mediate R³ Selected ¹H NMR data(CD₃OD) 5 2-F, 4-Cl, 5-F 7.11(dd,1H, J=8.9, 6.4Hz), 7.03(dd, 1H, J=9.0, 6.6) 6 2-F, 5-Cl 7.27(dd, 1H,J=6.4, 2.5Hz), 7.21(m, 1H), 7.03(t, 1H, J=9.2Hz) 7 2-Me, 5-Cl 7.16(d,1H, J=1.8Hz), 7.11–7.07(m, 2H), 2.34(s, 3H) 8 2-Cl, 5-Cl 7.34(d, 1H,J=9.0), 7.33(d, 1H, J=2.1Hz), 7.21(dd, 1H, J=8.5, 2.5Hz) 9 2-F, 3-Cl,6-F 7.35(td, 1H, J=8.5, 5.8Hz), 6.95(t, 1H, J=8.5Hz) 10 3-Cl, 4-F7.33(d, 1H, J=6.9Hz), 7.19–7.11(m, 2H) 11 2-F, 3-F, 6-F 7.18–7.12(m,1H), 6.91(m, 1H) 12 2-F, 4-F, 6-F 6.81(t, 2H, J=8.4Hz) 13 2-OCH₂Ph, 5-F7.49(d, 2H, J=7.6Hz), 7.38(t, 2H, J=7.3Hz), 7.30(t, 1H, J=7.3Hz), 6.96–6.89(m, 3H), 5.11(d, 1H, J=11.7Hz), 5.08(d, 1H, J=11.9Hz)

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-methyl-2H-1,4diazepin-2-onehydrochloride

Step A: Methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alaninate

To a stirred suspension of D-alanine methyl ester hydrochloride (2.0 g)and 5N aqueous sodium hydroxide solution (2.9 mL) in water (15 mL) at 0°C., acrylonitrile (1.1 mL) was added. The resultant mixture was stirredat 70° C. for 3.5 h and cooled to room temperature. Di-tert butyldicarbonate (30 mL) was added and the reaction mixture stirred for twodays. The reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The organic layerwas separated, washed with brine, dried over anhydrous sodium sulfateand concentrated. The residue was purified by flash columnchromatography (silica, ethyl acetate/hexane 2:3) to yield methylN-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alaninate.

Step B: Methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate

To a solution of methylN-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alaninate (1.5 g) in ethanol(80 mL) and chloroform (1.4 mL) was added platinum oxide (350 mg), andthe reaction mixture was stirred over an atmosphere of hydrogen for 16hr. The mixture was filtered through Celite, and the Celite washed withmethanol and dichloromethane. The filtrate was concentrated to givemethyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate as an oilyresidue.

Step C: tert-Butyl(2R)-Hexahydro-2-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate

To a 2M solution of trimethylaluminum in dichloromethane (30 mL) wasadded slowly a solution of methylN-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate (11.5 g) indichloromethane. The reaction mixture was stirred at room temperaturefor four days and then poured into a flask containing 30 g of Celite.The mixture was stirred and quenched by the slow addition of ˜10 mL ofsaturated aqueous ammonium chloride solution. Sodium sulfate (20 g) andmethanol (50 mL) were added. The mixture was stirred for 1 h, thenfiltered. The solids were washed with 5% methanol/dichloromethane. Thefiltrate was concentrated. The residue was purified by flashchromatography (silica gel, eluting sequentially with 4, 6, 7 and 12% of10:1 methanol/aqueous concentrated ammonium hydroxide indichloromethane) to provide the title compound containing less than 3%of the (3S)-isomer.

LC/MS 228.9 (M+1).

Step D: (3R)-Hexahydro-3-methyl-2H-1,4-diazepin-2-one hydrochloride

tert-Butyl (2R)-Hexahydro-2-methyl-3-oxo-1H-1,4-diazepine-1-carboxylateobtained in the previous step was dissolved in 4M hydrogen chloride indioxane and evaporated after 2.5 h to yield the hydrochloride salt ofthe desired compound.

Step E:(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2H-1,4-diazepin-2-one

To a solution of N-methylmorpholine (0.38 μL) and(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid (1.0 g) in 20 mL of dichloromethane at −20° C. was added isobutylchloroformate (0.39 mL). The resultant mixture was stirred for 1 h.(3R)-hexahydro-3-methyl-2H-1,4-diazepin-2-one hydrochloride (500 mg) andN-methylmorpholine (0.40 mL) in dichloromethane (5 mL) and DMF (8 mL)were added. The mixture was stirred for 28 h, initially at −20° C. andthen with slow warming to ambient temperature. The reaction was quenchedby the addition of saturated ammonium chloride solution and extractedsequentially with dichloromethane and ethyl acetate. The combinedorganic layer was washed sequentially with water and brine, dried oversodium sulfate, and concentrated. The residue was purified bychromatography (silica gel, 3 to 7% 10:1 methanol/concentrated ammoniumhydroxide in dichloromethane) to afford the coupled product. This wasfurther purified by dissolving the product in a mixture of ethanol (7.5mL) and hexane (16 mL) at 50° C. The solution was allowed to cool toambient temperature overnight, and then placed in the refrigerator for 3h. The solid was collected and washed with cold 5% ethanol/hexane togive the title compound.

Step F:(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2H-1,4-diazepin-2-onehydrochloride

(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2H-1,4-diazepin-2-onefrom Step E was treated with 4N hydrogen chloride in dioxane, stirredfor 2.5 h and evaporated to yield the title compound. LC/MS 344.1 (M+1).

4-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]hexahydro-1-methyl-2H-1,4-diazepin-2-onehydrochloride

Step A: Methyl N-(3-Aminopropyl)-N-(tert-butoxycarbonyl)glycinate

The title compound was prepared from glycine methyl ester hydrochloridefollowing the methods described in Example 1, Steps A–B.

LC/MS 241.0 (M+1).

Step B: tert-Butyl Hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate

To a solution of methylN-(3-aminopropyl)-N-(tert-butoxycarbonyl)glycinate (10.2 g) intetrahydrofuran (THF)/methanol (2/1, 300 mL) was added 1M aqueouslithium hydroxide solution (60 mL). The resultant mixture was stirred atroom temperature overnight. An additional 20 mL of 1M aqueous lithiumhydroxide solution was added and the mixture was stirred for 6 h.Solvent was removed under reduced pressure, and the residue wasdissolved in 50 mL of methanol and 200 mL of toluene and concentrated invacuo. To the residue in dichloromethane (300 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 9.6 g) and1-hydroxybenzotriazole (HOBT, 6.8 g). The mixture was stirred at roomtemperature for three days, then treated with saturated aqueous ammoniumchloride solution and extracted with three portions of ethyl acetate.The combined organics were washed with brine, dried over sodium sulfateand concentrated. The residue was purified by chromatography (silicagel, 4 to 5% methanol/aqueous ammonium hydroxide (10:1) indichloromethane) to yield the title compound. LS/MS 215.0 (M+1).

Step C: tert-ButylHexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate

Sodium hydride (103 mg) was added to a stirred solution of tert-butylhexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate in DMF (5 mL) at 0° C.After 1 h, iodomethane (0.15 mL) was added, and the resultant mixturewas stirred at 0° C., then room temperature overnight. It was dilutedwith saturated aqueous ammonium chloride solution and extracted withethyl acetate. The organic layer was separated, washed sequentially withsaturated aqueous sodium bicarbonate solution and brine, dried oversodium sulfate, and concentrated to give the product, which was usedwithout further purification.

Step D: Hexahydro-1-methyl-2H-1,4-diazepizn-2-one hydrochloride

tert-Butyl hexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylateobtained in Example 2, Step C was dissolved in 4M hydrogen chloride indioxane and evaporated after 2.5 h to yield the title compound.

Step E:4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoyl]hexahydro-1-methyl-2H-1,4-diazepin-2-one

To a stirred mixture of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid(40 mg), EDC (29 mg), and HOBT (21 mg) in dichloromethane was addedtriethylamine (0.042 mL) and hexahydro-1-methyl-2H-1,4-diazepin-2-onehydrochloride (33 mg). The resultant mixture was stirred at ambienttemperature overnight and then concentrated. The residue was purified bypreparative TLC (silica gel, 8% 10:1 methanol/concentrated ammoniumhydroxide in dichloromethane) to yield the title compound.

Step D:4-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]hexahydro-1-methyl-2H-1,4-diazepin-2-one

(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2H-1,4-diazepin-2-onefrom Step E was treated with 4N hydrogen chloride in dioxane, stirredfor 4 h and evaporated to yield the title compound.

LC/MS 326.0 (M+1).

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-benzylhexahydro-1-methyl-2H-1,4-diazepin-2-onehydrochloride

Step A: tert-Butyl2-Benzylhexahydro-4-methyl-3-oxo-H-1,4-diazepine-1-carboxylate

To a stirred solution of tert-butylhexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate, prepared asdescribed in Example 2, Step C (180 mg), in THF (8 mL) at −78° C. wasadded a solution of lithium diisopropylamide (LDA) (1.5M in cyclohexane,0.53 mL). After the mixture stirred for 40 min, benzyl bromide (0.28 mL)was added. The resultant mixture continued to be stirred at −78° C. for6 h. Then the reaction mixture was diluted with saturated aqueousammonium chloride solution, and extracted with ethyl acetate. Theorganic layer was washed sequentially with saturated aqueous sodiumbicarbonate solution and brine, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by chromatography (silica gel, 2%methanol/dichloromethane) to yield the title compound.

Step B: 3-Benzylhexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride

tert-Butyl2-benzylhexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate obtainedin Step A was dissolved in 4M hydrochoride in dioxane and evaporatedafter 2.5 h to yield the hydrochloride salt of the desired compound.

Step C:(3R)-4-[(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-benzylhexahydro-1-methyl-2H-1,4-diazepin-2-one

N-Methylmorpholine (0.048 mL) and isobutyl chloroformate (0.026 mL) wereadded to a stirred solution of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid (67 mg) in THF (1 mL) at −20° C. and the resultant mixture wasstirred for 1 h. 3-Benzylhexahydro-1-methyl-2H-1,4-diazepin-2-onehydrochloride obtained in Step B above (48 mg) and N-methylmorpholine(0.024 mL) in DMF (1 mL) were added. The mixture was stirred for 30 minat −20° C. and for 36 h at ambient temperature, and then evaporated. Theresidue was treated with saturated aqueous ammonium chloride solution,extracted with ethyl acetate, and the organic extract evaporated. Theproduct obtained was purified by preparative TLC (silica gel,methanol/concentrated ammonium hydroxide/dichloromethane 4.4:0.1:95.5)to obtain the coupled product as a mixture of diastereomers. The isomerswere resolved by HPLC (ChiralPAK AD, 14% ethanol/bexane) and the fastereluting (R,S)-isomer and slower eluting (R,R)-isomer were collected.

Step D:(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-benzylhexahydro-1-methyl-2H-1,4-diazepin-2-onehydrochloride

The title compound from Step C was dissolved in 4M hydrogen chloride indioxane and evaporated after 2.5 h to yield the desired product.

LC/MS 434.1 (M+1).

(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one

Step A: tert-Butyl4-[(Benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate

The title compound was prepared from tert-butylhexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate (Example 2, Step B) andbenzyl chloromethyl ether essentially following the method described inExample 2, Step C.

Step B: tert-Butyl4-[(Benzyloxy)methyl]hexahydro-3-oxo-2-[4-(trifluoromethoxy)benzyl]-1H-1,4-diazepine-1-carboxylate

The title compound was prepared from tert-butyl4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate and4-(trifluoromethoxy)benzylbromide essentially following the proceduredescribed in Example 3, Step 1.

Step C: tert-ButylHexahydro-3-oxo-2-[4-(trifluoromethoxy)benzyl]-H-1,4-diazepine-1-carboxylate

To a solution of tert-butyl4-[(benzyloxy)methyl]hexahydro-3-oxo-2-[4-(trifluoromethoxy)benzyl]-1H-1,4-diazepine-1-carboxylate(520 mg) in ethanol (17 mL) was added 10% palladium on carbon (300 mg).The reaction mixture was stirred for 22 h under an atmosphere ofhydrogen. A few drops of water were added and stirring continued for anadditional 20 h. The mixture was filtered through Celite, and the Celitewashed with ethyl acetate. The filtrate was evaporated under reducedpressure. The residue was purified by flash chromatography on a Biotage®apparatus (silica gel; methanol/concentrated aqueous ammonium hydroxidesolution/dicholoromethane 1.5:0.1:98.4). The product obtained wasdissolved in toluene and refluxed for 3 h. Evaporation under vacuumyielded the title compound, which was used in the next step withoutfurther purification.

Step D: Hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-onehydrochloride

tert-Butylhexahydro-3-oxo-2-[4-(trifluoromethoxy)benzyl]-1H-1,4-diazepine-1-carboxylatewas dissolved in 4M hydrogen chloride in dioxane and after 2.5 hevaporated to yield the desired product.

Step E:(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one

N-Methylmorpholine (0.072 mL) and isobutyl chloroformate (0.039 mL) wereadded to a stirred solution of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid (95 mg) in dichloromethane (5 mL) at −20° C. and the resultantmixture was stirred for 30 min.Hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-onehydrochloride obtained in Step D (91 mg) and IV-methylmorpholine (0.036mL) were added. The reaction mixture was stirred for 30 min at −20° C.and 2 h at ambient temperature and then evaporated. The residue waspurified by preparative TLC (silica gel, methanol/saturated aqueousammonium hydroxide/dichloromethane 4.4:0.1:95.5), and the isomers weresubsequently resolved by HPLC (ChiralPAK OD, 7% ethanol/hexane) toprovide the slower eluting (R,R)-isomer.

Step F:(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-onehydrochloride

(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-onewas dissolved in 4M hydrogen chloride in dioxane and evaporated after2.5 h to yield the desired product. LC/MS 504.2 (M+1).

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-1-tert-butylhexahydro-3-methyl-2H-1,4-diazepin-2-onehydrochloride

Step A: N-(tert-Butyl)-N-(2-cyanoethyl)-2-oxopropanamide

A solution of benzotriazole (2.4 g, 20 mmol) and thionyl chloride (1.5mL) in dichloromethane (10 mL) was added dropwise to a stirred solutionof pyruvic acid in dichloromethane (10 mL) and the mixture was stirredfor ten min. The precipitate formed was filtered and washed withdichloromethane. The filtrate was treated with magnesium sulfate,filtered, and the filtrate was stirred overnight with a solution of3-(tert-butylamino)propionitrile dissolved in dichloromethane (10 mL).The reaction mixture was treated with saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate, filtered, evaporated andpurified by Biotage® flash chromatography (silica gel, ethylacetate/hexane 1:1) to yield the desired product as an oil.

¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.45 (s, 3H), 2.74 (t, J=7.4 Hz,2H), 3.6 (board, 2H).

Step B: 1-tert-Butyl-hexahydro-3-methyl-2H-1,4-diazepin-2-one

N-(tert-butyl)-N-(2-cyanoethyl)-2-oxopropanamide obtained in Step A (440mg) and platinum oxide (60 mg) were suspended in ethyl alcohol (40 mL)containing chloroform (0.3 mL) and mixed on a Parr shaker over anatmosphere of hydrogen at 40 psi for 16 h. The mixture was filtered, thecatalyst was washed with methanol/dichloromethane (10:90) and thecombined filtrate was evaporated and purified by Biotage® flashchromatography (silica gel, 5–10% methanol/dichloromethane) to yield thedesired product.

¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6.6, 3H), 1.43 (s, 9H), 1.5 (m,1H), 1.7 (m, 1H), 2.9 (m, 1H), 3.2 (m, 1H), 3.4 (m, 1H.), 3.6 (m, 2H).LC/MS 185.2 (M+1).

Step C:(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-1-tert-butyl-hexahydro-3-methyl-2H-1,4-diazepin-2-one

The title compound was prepared from(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid and 1-tert-butyl-hexahydro-3-methyl-2H-1,4-diazepin-2-one by themethod described in Example 3, Step C and D. LC/MS 400.1 (M+1).

4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-5-methyl-2H-1,4-diazepin-2-one hydrochloride

Step A: Hexahydro-5-methyl-2H-1,4-diazepin-2-one

The title compound was prepared from crotononitrile essentiallyfollowing the procedures out lined in Example 2, Steps A and B.

Step B:4-[(3R)-3-amino-4-(2,4,5-trifluorolphenyl)butanoyl]hexahydro-5-methyl-2H-1,4-diazepin-2-one

The title compound was prepared from(3R)-3-[(tert-butoxycarbonyl)amino]4-(2,4,5-trifluorophenyl)butanoicacid hexahydro-5-methyl-2H-1,4-diazepin-2-one by the method described inExample 3, Step C and D.

LC/MS 344.1 (M+1).

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[(1-oxidopyridin-2-yl)methyl]-2H-1,4-diazepin-2-one,trifluoroacetic acid salt

Step A:(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[(1-oxidopyridin-2-yl)methyl]-2H-1,4-diazepin-2-one

The title compound was prepared essentially following the proceduresdescribed in Example 4, Steps A to E.

Step B:(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[(1-oxidopyridin-2-yl)methyl]-2H-1,4-diazepin-2-one,trifluoroacetic acid salt

To a solution of(3R)-4-[(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[(1-oxidopyridin-2-yl)methyl]-2H-1,4-diazepin-2-one(20 mg, 0.038 mmol) in dichloromethane (2.5 mL) at 0° C. was added mCPBA(28 mg, 0.096 mmol) and the reaction mixture was stirred overnight atambient temperature. The solution was treated with saturated aqueoussodium bicarbonate solution and extracted with dichloromethane. Theorganic phase was separated, dried over anhydrous sodium sulfate,filtered and evaporated. The residue was purified by preparative TLC(silica, 11:89 10% ammonia in methanol/dichloromethane) to yield theN-BOC protected pyridine N-oxide. Deprotection with trifluoroaceticacid-dichloromethane (1:1) at ambient temperature for 1 h followed byconcentration gave the desired product. MS 437.2 (M+1).

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[(1-oxidopyridin-3-yl)methyl]-2H-1,4-diazepin-2-one,trifluoroacetic acid salt

The title compound was prepared essentially following the proceduresdescribed in Example 7. MS 437.2 (M+1).

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-(1H-pyrazol-1-ylmethyl)-2H-1,4-diazepin-2-one,trifluoroacetic acid salt

Step A: tert-Butyl4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate

The title compound was prepared from tert-butylhexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate (Example 2, Step B) andbenzyl chloromethyl ether essentially following the method described inExample 2, Step C.

Step B: tert-Butyl4-[(benzyloxy)methyl]hexahydro-2-methylene-3-oxo-1,4-diazepine-1-carboxylate

The title was prepared from tert-butyl4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate andbenzyl chloromethyl ether essentially following the procedure describedin Example 3, Step 1.

Step C: tert-Butyl 4-1(benzyloxy)methyl]hexahydro-2-(1H-pyrazol-1-ylmethyl)-3-oxo-1,4-diazepine-1-carboxylate

To a solution of pyrazole (258 mg, 3.78 mmol) in 10 mL of DMF at 0° C.was added sodium hydride (60%, 91 mg). The resultant mixture was stirredfor 30 min and then the product from Step B (655.4, 1.89 mmol) wasadded. The reaction was stirred at ambient temperature overnight andquenched by the addition of water. The aqueous mixture was extractedwith three portions of ethyl acetate. The combined organic phases wereconcentrated. Purification by flash chromatography on a Biotage®apparatus (silica gel, 40–80% ethyl acetate/hexane gradient) gave thetitle compound.

Step D: 3-(1H-pyrazol-1-ylmethyl)-1,4-diazepan-2-one

The product from Step C was treated with trifluoroacetic acid. Thereaction was stirred at ambient temperature overnight and thenconcentrated. The residue was dissolved in toluene and heated at refluxfor 3 h. Purification by flash chromatography on a Biotage® apparatus(silica gel, 5–15% of 10:1 methanol/ammonium hydroxide indichloromethane) gave the title compound.

Step E:(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-(1H-pyrazol-1-ylmethyl)-2H-1,4-diazepin-2-one, trifluoroacetic acid salt

The title compound was prepared from the product from Step D and(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid essentially following the coupling method described in Example 4,Step E. Purification by preparative TLC (silica, 1:9ethanol/dichloromethane) gave the N-BOC product as a mixture ofdiastereomers. HPLC (chiralcell OJ column, 7% ethanol/hexane) providedthe individual diastereomers. Deprotection with 1:1 trifluoroaceticacid/dichloromethane for 1 h at ambient temperature followed byconcentration gave the individual diastereomers of the title compound.MS 410.2 (M+1).

Essentially following the procedures outlined for the preparation ofExamples 1–9, the compounds in Table 2 were prepared.

TABLE 2

MS Example R³ R⁴ R¹ (M + 1) 10 2-F, 5-F Me H 326.1 11 2-F, CH₂-cPr H384.1 4-F, 5-F 12 2-F, Me Me 358.1 4-F, 5-F 13 2-F, 5-F Me Et 354.1 142-F, Me cPr 384.3 4-F, 5-F 15 2-F, 5-F Me CH₂CO₂Me 398.1 16 2-F, MeCH₂CH₂OH 388.1 4-F, 5-F 17 2-F, Me CH₂CH₂OCH₂C₆H₅ 478.2 4-F, 5-F 18 2-F,Et Me 372.2 4-F, 5-F 19 2-F, 5-F Et Me 354.1 20 2-F, CH₂OH Me 374.0 4-F,5-F 21 2-F CH₂Ph Me 398.2 22 3-F, 4-F CH₂Ph Me 416.2 23 2-F, CH₂OCH₂PhMe 464.2 4-F, 5-F 24 2-F, Et H 358.1 4-F, 5-F 25 2-F, CH₂Ph H 420.1 4-F,5-F 26 3-F, 4-F CH₂Ph H 402.1 27 2-F, 5-F CH₂(4-OCF₃—Ph) H 486.1 28 2-F,CH₂(3-OCF₃—Ph) H 504.2 4-F, 5-F 29 2-F, CH₂CH(CH₃)₂ Me 400.2 4-F, 5-F 302-F, CH₂(3-CF₃, H 556.2 4-F, 5-F 5-CF₃—Ph) 31 2-F, 5-F H H 312.2 32 2-F,CH₂(2-CF₃—Ph) H 488.1 4-F, 5-F 33 2-F, CH₂(2-Cl—Ph) H 454.0 4-F, 5-F 342-F, CH₂(2-CH₃—Ph) H 434.1 4-F, 5-F 35 2-F, CH₂(2-CH₃, H 448.2 4-F, 5-F5-CH₃—Ph) 36 2-F, Me CHMe₂ 386.2 4-F, 5-F 37 2-F, CH₂(2-Ph—Ph) H 496.34-F, 5-F 38 2-F, CH₂(2-F, 5-F—Ph) H 456.1 4-F, 5-F 39 2-F, CH₂(2-F—Ph) H438.1 4-F, 5-F 40 2-F, Me CH₂CF₃ 426.1 4-F, 5-F 41 2-F, CH₂(2-F, 3-F—Ph)H 456.2 4-F, 5-F 42 2-F, CH₂(3-pyridyl) H 421.1 4-F, 5-F 43 2-F,CH₂(2-F—Ph) CH₂CH₂CH₃ 480.2 4-F, 5-F 44 2-F, CH₂(4-pyridyl) H 421.1 4-F,5-F 45 2-F, CH₂(2-F—Ph) Me 452.2 4-F, 5-F 46 2-F, CH₂(2-pyridyl) H 421.24-F, 5-F 47 2-F, CH₂(2-F, 6-F—Ph) H 456.3 4-F, 5-F 48 2-F, CH₂CF₃ H412.3 4-F, 5-F

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any of the compounds of thepresent invention, 268 mg microcrystalline cellulose, 20 mg ofcroscarmellose sodium, and 4 mg of magnesium stearate. The active,microcrystalline cellulose, and croscarmellose are blended first. Themixture is then lubricated by magnesium stearate and pressed intotablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof; wherein each n isindependently 0, 1, or 2; Ar is phenyl substituted with one to five R³substituents; R¹ is selected from the group consisting of hydrogen,C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted with one tofive substituents independently selected from halogen, hydroxy, C₁₋₆alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy, whereinalkoxy is unsubstituted or substituted with one to five halogens,(CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted with one tofive substituents independently selected from halogen, CN, hydroxy, R²,OR², NHSO₂R², NR²SO₂R², SO₂R², CO₂H, and C₁₋₆ alkyloxycarbonyl,(CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or substitutedwith one to three substituents independently selected from hydroxy,halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five halogens,(CH₂)_(n)-heterocyclyl, wherein heterocyclyl is unsubstituted orsubstituted with one to three substituents independently selected fromoxo, hydroxy, halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl andalkoxy are unsubstituted or substituted with one to five halogens,(CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is unsubstituted orsubstituted with one to three substituents independently selected fromhalogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxyare unsubstituted or substituted with one to five halogens; and whereinany methylene (CH₂) carbon atom in R¹ is unsubstituted or substitutedwith one to two groups independently selected from halogen, hydroxy, andC₁₋₄ alkyl unsubstituted or substituted with one to five halogens; eachR³ is independently selected from the group consisting of hydrogen,halogen, cyano, hydroxy, C₁₋₆ alkyl, unsubstituted or substituted withone to five halogens, C₁₋₆ alkoxy, unsubstituted or substituted with oneto five halogens, carboxy, alkoxycarbonyl, amino, NHR², NR²R², NHSO₂R²,NR²SO₂R², NHCOR², NR²COR², NHCO₂R², NR²CO₂R², SO₂R², SO₂NH₂, SO₂NHR²,and SO₂NR²R²; each R² is independently C₁₋₆ alkyl, unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, CO₂H, and C₁₋₆ alkyloxycarbonyl; R⁴ and R⁵ are independentlyselected from the group consisting of: hydrogen, cyano, carboxy, C₁₋₆alkyloxycarbonyl, C₁₋₁₀ alkyl, unsubstituted or substituted with one tofive substituents independently selected from halogen, hydroxy, C₁₋₆alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy, whereinalkoxy is unsubstituted or substituted with one to five halogens,(CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted with one tofive substituents independently selected from halogen, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)-heteroaryl, whereinheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from hydroxy, halogen, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)-heterocyclyl, whereinheterocyclyl is unsubstituted or substituted with one to threesubstituents independently selected from oxo, hydroxy, halogen, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)—C₃₋₆ cycloalkyl,wherein cycloalkyl is unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)CONR⁶R⁷, wherein R⁶ andR⁷ are independently selected from the group consisting of hydrogen,tetrazolyl, thiazolyl, (CH₂)_(n)-phenyl, (CH₂)_(n)—C₃₋₆ cycloalkyl, andC₁₋₆ alkyl, wherein alkyl is unsubstituted or substituted with one tofive halogens and wherein phenyl and cycloalkyl are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxyare unsubstituted or substituted with one to five halogens; or whereinR⁶ and R⁷ together with the nitrogen atom to which they are attachedform a heterocyclic ring selected from azetidine, pyrrolidine,piperidine, piperazine, and morpholine; and wherein said heterocyclicring is unsubstituted or substituted with one to five substituentsindependently selected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted withone to five halogens; and wherein any methylene (CH₂) carbon atom in R⁴or R⁵ is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five halogens; and R⁸ and R⁹are each independently hydrogen or C₁₋₆ alkyl.
 2. The compound of claim1 of the formula Ia:

wherein the carbon atom marked with an * has the R configuration and Ar,R¹, R⁴, R⁵, R⁸, and R⁹ are as defined in claim
 1. 3. The compound ofclaim 1 wherein R³ is selected from the group consisting of hydrogen,halogen, cyano, hydroxy, C₁₋₆ alkyl, unsubstituted or substituted withone to five halogens, and C₁₋₆ alkoxy, unsubstituted or substituted withone to five halogens.
 4. The compound of claim 3 wherein R³ is selectedfrom the group consisting of hydrogen, fluoro, chloro, bromo,trifluoromethyl, and methyl.
 5. The compound of claim 4 wherein R³ ishydrogen, chloro, or fluoro.
 6. The compound of claim 1 wherein R¹ isselected from the group consisting of: hydrogen, C₁₋₆ alkyl, whereinalkyl is unsubstituted or substituted with one to five substituentsindependently selected from halogen, hydroxy, C₁₋₆ alkoxy, carboxy, C₁₋₆alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy, wherein alkoxy isunsubstituted or substituted with one to five halogens, (CH₂)_(n)—C₃₋₆cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with oneto three substituents independently selected from halogen, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens; and wherein any methylene (CH₂)carbon atom in R¹ is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five halogens.
 7. The compoundof claim 6 wherein R¹ is selected from the group consisting of hydrogen,C₁₋₄ alkyl, 2,2,2-trifluoroethyl, methoxycarbonylmethyl, carboxymethyl,hydroxyethyl, benzyloxymethyl, benzyloxyethyl, and cyclopropyl.
 8. Thecompound of claim 7 wherein R¹ is selected from the group consisting ofhydrogen, methyl, tert-butyl, and cyclopropyl.
 9. The compound of claim1 wherein R⁴ and R⁵ are independently selected from the group consistingof: hydrogen, C₁₋₁₀ alkyl, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, C₁₋₆ alkoxy,carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy, wherein alkoxyis unsubstituted or substituted with one to five halogens,(CH₂)_(n)-aryl, wherein aryl is unsubstituted or substituted with one tofive substituents independently selected from halogen, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)-heteroaryl, whereinheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from hydroxy, halogen, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)-heterocyclyl, whereinheterocyclyl is unsubstituted or substituted with one to threesubstituents independently selected from oxo, hydroxy, halogen, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, (CH₂)_(n)—C₃₋₆ cycloalkyl,wherein cycloalkyl is unsubstituted or substituted with one to threesubstituents independently selected from halogen, hydroxy, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, wherein any methylene (CH₂)carbon atom in R⁴ or R⁵ is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five halogens.
 10. The compoundof claim 9 wherein R⁴ and R⁵ are independently selected from the groupconsisting of: hydrogen, C₁₋₆ alkyl, unsubstituted or substituted withone to five substituents independently selected from halogen, hydroxy,C₁₋₆ alkoxy, carboxy, C₁₋₆ alkyloxycarbonyl, and phenyl-C₁₋₃ alkoxy,wherein alkoxy is unsubstituted or substituted with one to fivehalogens, (CH₂)_(n)-aryl, wherein aryl is unsubstituted or substitutedwith one to five substituents independently selected from halogen,hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five halogens,(CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or substitutedwith one to three substituents independently selected from hydroxy,halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five halogens, (CH₂)_(n)—C₃₋₆cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with oneto three substituents independently selected from halogen, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, and wherein any methylene (CH₂)carbon atom in R⁴ or R⁵ is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkylunsubstituted or substituted with one to five halogens.
 11. The compoundof claim 10 wherein R⁴ and R⁵ are independently selected from the groupconsisting of: hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂-cyclopropyl,CH₂-cyclohexyl, CH₂OCH₂Ph, CH₂OH CH₂Ph, CH₂(3-OCF₃-Ph), CH₂(4-OCF₃-Ph),CH₂(3-CF₃,5-CF₃-Ph), CH₂(2-CF₃-Ph), CH₂(2-Cl-Ph), CH₂(2-Me-Ph),CH₂(2-Me,5-Me-Ph), CH₂(2-Ph-Ph), CH₂(2-F,5-F-Ph), CH₂(2-F-Ph),CH₂(2-F,3-F-Ph), CH₂(2-pyridinyl), CH₂(3-pyridinyl), CH₂(4-pyridinyl),CH₂(1-oxidopyridin-2-yl), CH₂(1-oxidopyridin-3-yl),CH₂(1H-pyrazol-1-yl), CH₂(2-F,6-F-Ph), and CH₂CF₃.
 12. The compound ofclaim 11 wherein R⁵ is hydrogen.
 13. The compound of claim 1 wherein R⁸and R⁹ are independently selected from hydrogen and methyl.
 14. Thecompound of claim 13 wherein R⁸ and R⁹ are hydrogen.
 15. The compound ofclaim 1 wherein R¹ is selected from the group consisting of hydrogen,C₁₋₄ alkyl, 2,2,2-trifluoroethyl, methoxycarbonylmethyl, carboxymethyl,hydroxyethyl, benzyloxymethyl, benzyloxyethyl, and cyclopropyl; R³ ishydrogen, chloro, or fluoro; R⁴ is selected from the group consistingof: hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂-cyclopropyl, CH₂-cyclohexyl,CH₂OCH₂Ph, CH₂OH CH₂Ph, CH₂(3-OCF₃-Ph), CH₂(4-OCF₃-Ph), andCH₂(3-CF₃,5-CF₃-Ph) CH₂(2-CF₃-Ph), CH₂(2-Cl-Ph), CH₂(2-Me-Ph),CH₂(2-Me,5-Me-Ph), CH₂(2-Ph-Ph), CH₂(2-F,5-F-Ph), CH₂(2-F-Ph),CH₂(2-F,3-F-Ph), CH₂(2-pyridinyl), CH₂(3-pyridinyl), CH₂(4-pyridinyl),CH₂(1-oxidopyridin-2-yl), CH₂(1-oxidopyridin-3-yl),CH₂(1H-pyrazol-1-yl), CH₂(2-F,6-F-Ph), and CH₂CF₃; and R⁸ and R⁹ arehydrogen.
 16. The compound of claim 15 wherein R⁵ is hydrogen.
 17. Thecompound of claim 15 which is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim15 of structural formula Ib selected from the group consisting of Ib

R³ R⁴ R¹ 2-F, 5-F Me H 2-F, 4-F, 5-F CH₂-cPr H 2-F, 4-F, 5-F Me Me 2-F,5-F Me Et 2-F, 4-F, 5-F Me cPr 2-F, 5-F Me CH₂CO₂Me 2-F, 4-F, 5-F MeCH₂CH₂OH 2-F, 4-F, 5-F Me CH₂CH₂OCH₂C₆H₅ 2-F, 4-F, 5-F Et Me 2-F, 5-F EtMe 2-F, 4-F, 5-F CH₂OH Me 2-F CH₂Ph Me 3-F, 4-F CH₂Ph Me 2-F, 4-F, 5-FCH₂OCH₂Ph Me 2-F, 4-F, 5-F Et H 2-F, 4-F, 5-F CH₂Ph H 3-F, 4-F CH₂Ph H2-F, 5-F CH₂(4-OCF₃—Ph) H 2-F, 4-F, 5-F CH₂(3-OCF₃—Ph) H 2-F, 4-F, 5-FCH₂CH(CH₃)₂ Me 2-F, 4-F, 5-F CH₂(3-CF₃, 5-CF₃—Ph) H 2-F, 5-F H H 2-F,4-F, 5-F CH₂(2-CF₃—Ph) H 2-F, 4-F, 5-F CH₂(2-Cl—Ph) H 2-F, 4-F, 5-FCH₂(2-CH₃—Ph) H 2-F, 4-F, 5-F CH₂(2-CH₃, 5-CH₃—Ph) H 2-F, 4-F, 5-F MeCHMe₂ 2-F, 4-F, 5-F CH₂(2-Ph—Ph) H 2-F, 4-F, 5-F CH₂(2-F, 5-F—Ph) H 2-F,4-F, 5-F CH₂(2-F—Ph) H 2-F, 4-F, 5-F Me CH₂CF₃ 2-F, 4-F, 5-F CH₂(2-F,3-F—Ph) H 2-F, 4-F, 5-F CH₂(3-pyridyl) H 2-F, 4-F, 5-F CH₂(2-F—Ph)CH₂CH₂CH₃ 2-F, 4-F, 5-F CH₂(4-pyridyl) H 2-F, 4-F, 5-F CH₂(2-F—Ph) Me2-F, 4-F, 5-F CH₂(2-pyridyl) H 2-F, 4-F, 5-F CH₂(2-F, 6-F—Ph) H 2-F,4-F, 5-F CH₂CF₃ H

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition which comprises a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 20. A method for treating diabetes in a mammal inneed thereof which comprises the administration to the mammal of atherapeutically effective amount of a compound of claim
 1. 21. A methodfor treating non-insulin dependent (Type 2) diabetes in a mammal in needthereof which comprises the administration to the mammal of atherapeutically effective amount of a compound of claim
 1. 22. Acompound which is:

or a pharmaceutically acceptable salt thereof.
 23. A compound which is:

or a pharmaceutically acceptable salt thereof.
 24. A compound which is:

or a pharmaceutically acceptable salt thereof.
 25. A compound which is:

or a pharmaceutically acceptable salt thereof.